Abstract Brain trauma in humans may be a significant risk factor in developing Alzheimer's disease. A number of studies have shown the presence of A-beta plaques in postmortem brains of single-incidence brain trauma victims. A-beta is neurotoxic peptide that forms the plaques that are the major pathology in Alzheimer's disease. The production and accumulation of A-beta may be responsible for neuronal cell loss that occurs in the hours and days following brain trauma. However, why the production of A-beta increases following brain trauma is not yet known. By using animal models of brain trauma we can elucidate mechanisms involved in A-beta production, as well as understanding pathways involved in neuronal cell death following brain trauma. A-beta is formed when a transmembrane precursor protein is cleaved. Cholesterol is an integral membrane lipid and is found in high concentrations in the brain. In vitro, when cellular cholesterol levels increase, cleavage of the precursor protein to A-beta also increases. A decrease in cholesterol levels causes a decrease in A-beta formation. These results have been replicated with cholesterol lowering drugs in vivo. In humans, taking cholesterol lowering drugs may reduce the incidence of Alzheimer's disease. Traumatic brain trauma in rodents causes a chain of cell death, starting in the region of direct impact. As the cells die and degrade, their constituent parts are recycled. We hypothesize that this leads to a transient increase in cholesterol levels in cells immediately surrounding the injured area, and this increase is responsible for the acute increase in A-beta levels following brain trauma. We aim to test this hypothesis by 1) Measuring cholesterol-related regulatory proteins and the A-beta response following brain trauma in rodents and 2) attempting to intervene and inhibit these changes by using an LXR agonist (TO-901317) and a statin (lovastatin) prior to and following injury. We believe that TO-901317 will prevent cells surrounding the injured area from accepting cholesterol from damaged neurons, and that this will prevent the TBI-induced A-beta spike. Statins have previously been shown to be beneficial in cognitive recovery and lesion size following TBI, therefore we will examine the effects of lovastatin on both the cholesterol response to TBI, and its anti-inflammatory effects in an attempt to elucidate a possible mechanism of action. These studies aim to understand how A-beta is produced, and why brain injury can lead to production of the neurotoxin, A-beta Project Relevance This research aims to investigate how cholesterol homeostasis is altered following traumatic brain injury (TBI) in mice, and if this change in cholesterol is responsible for the increased production of Abeta that has been reported in this model. As CNS cholesterol is independent of fluctuations in peripheral cholesterol, it is difficult to examine the effects of cholesterol in the CNS independent of effects in the periphery. Using TBI as a model of dysfunctional intracerebral cholesterol homeostasis is a novel approach to examine how changes in CNS cholesterol alone can alter Abeta levels. Furthermore, the data we provide in this project will help determine the course of events following TBI, and the pathways identified may help guide future drug development studies. As such this project has multidisciplinary benefits and is relevant to the fields of CNS cholesterol, Alzheimer's disease and brain injury. [unreadable] [unreadable] [unreadable]